General information on the behavioral pharmacology of a drug in a pertinent species is necessary to evaluate quantitatively how the drug functions as a reinforcer or a punisher as well as to establish a profile of behavioral effects. Schedules of food presentation with both fixed-interval and fixed-ratio components have been used most frequently used in this type of study since they generate a wide range of rates and patterns of responding within a session and provide stable, long-term baselines for chronic studies in individual animals. The present project involves the assessment of both the acute and chronic effects of a variety of drugs on schedule-controlled behavior. We have recently shown while the calcium channel antagonists are effective in antagonizing the cardiovascular effects of cocaine, they do not significantly modify the direct behavioral effects of cocaine. This includes both the rate-increasing and rate-decreasing effects of cocaine. We have also completed a long-term study designed to determine whether tolerance to either the rate-increasing or rate-decreasing effects of cocaine could be observed using a second-order schedule where the animals were allowed as long a period of time as needed to complete the schedule requirements. Under these conditions, we did not observe any tolerance development to the effects of cocaine. We have also recently shown that the enhanced sensitivity which occurs to opioid antagonists is pharmacologically specific, with cross-sensitivity occurring only to pure opioid antagonists. Further, we have demonstrated that this enhanced sensitivity occurs to salivation produced by high doses of naltrexone. This result is important as it allows us to study the phenomenon of enhanced sensitivity independently of schedule-controlled behavior. In collaboration with Dr. Su in the Neuroscience branch we have shown that specific changes occur in opioid receptor binding following opioid antagonist treatment. In addition to their direct effects on behavior, drugs of abuse can also function as discriminative stimuli. Most of these studies are being performed in rats and we are studying the discriminative stimulus effects of cocaine and other psychomotor stimulants, opioids and the benzodiazepines. These studies are designed to characterize the relative potency and efficacy of test drugs to produce drug-like effects, and to evaluate the drug's mechanism of action at the receptor level. For example, we are currently conducting experiments to determine if calcium channel antagonists, which can block some of the physiological effects of opioids, might also antagonize the discriminative stimulus properties of these drugs. Similar studies are also underway in human subjects under the direction of Dr. Vaupel from the Neuroscience Branch.